Monocyclic β-lactam inhibitors of human leukocyte elastase. Stereospecific synthesis and activity of 3,4-disubstituted-2-azetidinones.

Inhibition of Elastase by N-Sulfonylaryl β-Lactams: Anatomy of a Stable Acyl−Enzyme Complex,

“…Kinetic studies indicating a bifurcating pathway (13) were consistent with this and other mechanisms involving partitioning of an intermediate between turnover and formation of a relatively stable enzyme-inhibitor complex (Scheme 1). Studies on β-lactams with a leaving group at the C-4 position demonstrated that the mechanism of elastase inhibition by monocyclic β-lactams is dependent upon both the substitution pattern and stereochemistry of the β-lactam template (15,16). For our studies on the factors governing the stability of acyl-enzyme complexes, we chose to examine the interaction of N-sulfonylaryl β-lactams, without a leaving group at the C-4 position, with PPE since it seemed likely that their mechanism of action is likely to be among the simplest of known β-lactam protease inhibitors.…”

Orally Active .beta.-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure-Activity Relationships for 3,3-Dialkylazetidin-2-ones

“…In vitro blood stability (¿1/2 < 6 h) and oral absorption in the marmoset were also demonstrated. 17 We then reasoned that a second 3/3alkyl group as in 3 might further enhance the /3-lactam stability and thus improve the oral absorption and pharmacokinetic properties. Herein we report in detail the development, stereoselective synthesis, and unexpected stereochemical requirements of 3,3-dialkylazetidin-2-one derivatives as stable, orally active HLE inhibitors.…”

“…The above differences in chemical shifts were easily used to determine the diastereomeric purities following the chromatographic separations of 15a,b, especially the difference in the C-4 hydrogens. These chemical shift differences were also evident in the acylated products [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and to a lesser extent in the carboxylic acid intermediates 14a,b.…”

Diastereoselective Conjugate Reduction and Enolate Trapping with Glyoxylate Imines. A Concise Approach to β-Lactams that Involves a Ternary Combination of Components

“…The general procedure was followed using 6b (0.37 g, 1 mmol): yield 0.19 g (73%); mp 102-104 °C (cyclohexane); [R] D 25 ) -136.3 (c ) 1.0, CH2Cl2); IR (KBr, υ cm -1 ) 1732 (CdO); MS(m/z, rel intensity) 263 (16.3), 149 (44.6), 134 (100.0); 1 H NMR (CDCl3, δ ppm) 1.11 (d, 3H, J ) 6.8 Hz), 1.56-1.98 (m, 2H), 3.54 (dt, 1H, J ) 6.0, 8.0 Hz), 3.81 (s, 3H), 3.83 (s, 3H), 4.63 (d, 1H, J ) 6.0 Hz), 6.89 (d, 2H, J ) 9.0 Hz), 7.26 (d, 2H, J ) 9.0 Hz); 13 C NMR (CDCl3, δ ppm) 169. 5,165.6,156.2,131.0,117.8,114.4,55.5,55.3,54.7,52.4,19.0. Anal.…”

“…Besides this significance, 3-alkyl-4-alkoxycarbonylazetidin-2-ones 2 are also excellent candidates for the development of synthetic inhibitors of elastase enzymes , of the latter are the L-652117 3 , compound 4 , and L-680,833 5 . Therefore, it is not surprising that a vast number of methods are now available for the stereoselective synthesis of monocyclic β-lactams .…”